Skip to main content
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1995 Apr;95(4):1650–1659. doi: 10.1172/JCI117840

Cisplatin-associated anemia: an erythropoietin deficiency syndrome.

P A Wood 1, W J Hrushesky 1
PMCID: PMC295669  PMID: 7706473

Abstract

Cisplatin-based therapy results in a cumulative anemia that is disproportionate to the effects on other blood cells. The severity of this treatment-induced anemia and the resultant transfusion requirement in cancer patients correlate with cisplatin-induced renal tubular dysfunction. Observed/expected serum erythropoietin (EPO) ratios decline with progressive cisplatin therapy and are proportionate to the degree of renal dysfunction. Recovery from anemia and of observed/expected serum EPO ratios in patients occurs after cessation of cisplatin therapy, along with restoration of renal tubular function. Creatinine clearance, however, remains permanently depressed. Cisplatin-treated rats develop progressive renal dysfunction and anemia that persists for many weeks, without effects on white blood cell counts. The anemia is also associated with a lack of expected EPO and reticulocyte response. With EPO administration, cisplatin-treated rats exhibit a greater reticulocyte response and hematocrit increment then non-cisplatin-treated rats given EPO, indicating minimal erythroid precursor cell damage from cisplatin. These results indicate the primary etiology of cisplatin-associated anemia is a transient, but persisting EPO deficiency state resulting from cisplatin-induced renal tubular damage, which can be prevented or treated by hormone (EPO) replacement.

Full text

PDF
1650

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Adamson J. W., Eschbach J., Finch C. A. The kidney and erythropoiesis. Am J Med. 1968 May;44(5):725–733. doi: 10.1016/0002-9343(68)90254-4. [DOI] [PubMed] [Google Scholar]
  2. Barton C. H., Pahl M., Vaziri N. D., Cesario T. Renal magnesium wasting associated with amphotericin B therapy. Am J Med. 1984 Sep;77(3):471–474. doi: 10.1016/0002-9343(84)90106-2. [DOI] [PubMed] [Google Scholar]
  3. Cascinu S., Fedeli A., Del Ferro E., Luzi Fedeli S., Catalano G. Recombinant human erythropoietin treatment in cisplatin-associated anemia: a randomized, double-blind trial with placebo. J Clin Oncol. 1994 May;12(5):1058–1062. doi: 10.1200/JCO.1994.12.5.1058. [DOI] [PubMed] [Google Scholar]
  4. Case D. C., Jr, Bukowski R. M., Carey R. W., Fishkin E. H., Henry D. H., Jacobson R. J., Jones S. E., Keller A. M., Kugler J. W., Nichols C. R. Recombinant human erythropoietin therapy for anemic cancer patients on combination chemotherapy. J Natl Cancer Inst. 1993 May 19;85(10):801–806. doi: 10.1093/jnci/85.10.801. [DOI] [PubMed] [Google Scholar]
  5. Cotes P. M., Pippard M. J., Reid C. D., Winearls C. G., Oliver D. O., Royston J. P. Characterization of the anaemia of chronic renal failure and the mode of its correction by a preparation of human erythropoietin (r-HuEPO). An investigation of the pharmacokinetics of intravenous erythropoietin and its effects on erythrokinetics. Q J Med. 1989 Feb;70(262):113–137. [PubMed] [Google Scholar]
  6. Dentino M., Luft F. C., Yum M. N., Williams S. D., Einhorn L. H. Long term effect of cis-diamminedichloride platinum (CDDP) on renal function and structure in man. Cancer. 1978 Apr;41(4):1274–1281. doi: 10.1002/1097-0142(197804)41:4<1274::aid-cncr2820410410>3.0.co;2-f. [DOI] [PubMed] [Google Scholar]
  7. Faquin W. C., Schneider T. J., Goldberg M. A. Effect of inflammatory cytokines on hypoxia-induced erythropoietin production. Blood. 1992 Apr 15;79(8):1987–1994. [PubMed] [Google Scholar]
  8. Fjeldborg P., Sørensen J., Helkjaer P. E. The long-term effect of cisplatin on renal function. Cancer. 1986 Nov 15;58(10):2214–2217. doi: 10.1002/1097-0142(19861115)58:10<2214::aid-cncr2820581009>3.0.co;2-i. [DOI] [PubMed] [Google Scholar]
  9. Friberg L., Vahter M. Assessment of exposure to lead and cadmium through biological monitoring: results of a UNEP/WHO global study. Environ Res. 1983 Feb;30(1):95–128. doi: 10.1016/0013-9351(83)90171-8. [DOI] [PubMed] [Google Scholar]
  10. Gandara D. R., Wold H., Perez E. A., Deisseroth A. B., Doroshow J., Meyers F., McWhirter K., Hannigan J., De Gregorio M. W. Cisplatin dose intensity in non-small cell lung cancer: phase II results of a day 1 and day 8 high-dose regimen. J Natl Cancer Inst. 1989 May 10;81(10):790–794. doi: 10.1093/jnci/81.10.790. [DOI] [PubMed] [Google Scholar]
  11. Getaz E. P., Beckley S., Fitzpatrick J., Dozier A. Cisplatin-induced hemolysis. N Engl J Med. 1980 Feb 7;302(6):334–335. doi: 10.1056/NEJM198002073020607. [DOI] [PubMed] [Google Scholar]
  12. Gonzales-Vitale J. C., Hayes D. M., Cvitkovic E., Sternberg S. S. The renal pathology in clinical trials of cis-platinum (II) diamminedichloride. Cancer. 1977 Apr;39(4):1362–1371. doi: 10.1002/1097-0142(197704)39:4<1362::aid-cncr2820390403>3.0.co;2-n. [DOI] [PubMed] [Google Scholar]
  13. Hart P., Farrell G. C., Cooksley W. G., Powell L. W. Enhanced drug metabolism in cigarette smokers. Br Med J. 1976 Jul 17;2(6028):147–149. doi: 10.1136/bmj.2.6028.147. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Hayes D. M., Cvitkovic E., Golbey R. B., Scheiner E., Helson L., Krakoff I. H. High dose cis-platinum diammine dichloride: amelioration of renal toxicity by mannitol diuresis. Cancer. 1977 Apr;39(4):1372–1381. doi: 10.1002/1097-0142(197704)39:4<1372::aid-cncr2820390404>3.0.co;2-j. [DOI] [PubMed] [Google Scholar]
  15. Hrushesky W. J., Borch R., Levi F. Circadian time dependence of cisplatin urinary kinetics. Clin Pharmacol Ther. 1982 Sep;32(3):330–339. doi: 10.1038/clpt.1982.168. [DOI] [PubMed] [Google Scholar]
  16. Hrushesky W. J., Levi F. A., Halberg F., Kennedy B. J. Circadian stage dependence of cis-diamminedichloroplatinum lethal toxicity in rats. Cancer Res. 1982 Mar;42(3):945–949. [PubMed] [Google Scholar]
  17. Hughes R. T., Cotes P. M., Pippard M. J., Stevens J. M., Oliver D. O., Winearls C. G., Royston J. P. Subcutaneous administration of recombinant human erythropoietin to subjects on continuous ambulatory peritoneal dialysis: an erythrokinetic assessment. Br J Haematol. 1990 Jun;75(2):268–273. doi: 10.1111/j.1365-2141.1990.tb02661.x. [DOI] [PubMed] [Google Scholar]
  18. Ishikawa T., Ali-Osman F. Glutathione-associated cis-diamminedichloroplatinum(II) metabolism and ATP-dependent efflux from leukemia cells. Molecular characterization of glutathione-platinum complex and its biological significance. J Biol Chem. 1993 Sep 25;268(27):20116–20125. [PubMed] [Google Scholar]
  19. James R. D., Wilkinson P. M., Belli F., Welch R., Cowan R. Recombinant human erythropoietin in patients with ovarian carcinoma and anaemia secondary to cisplatin and carboplatin chemotherapy: preliminary results. Acta Haematol. 1992;87 (Suppl 1):12–15. doi: 10.1159/000204782. [DOI] [PubMed] [Google Scholar]
  20. Johnson R. A., Waddelow T. A., Caro J., Oliff A., Roodman G. D. Chronic exposure to tumor necrosis factor in vivo preferentially inhibits erythropoiesis in nude mice. Blood. 1989 Jul;74(1):130–138. [PubMed] [Google Scholar]
  21. Kjellström T. Exposure and accumulation of cadmium in populations from Japan, the United States, and Sweden. Environ Health Perspect. 1979 Feb;28:169–197. doi: 10.1289/ehp.28-1637502. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Klassen D. K., Spivak J. L. Hepatitis-related hepatic erythropoietin production. Am J Med. 1990 Nov;89(5):684–686. doi: 10.1016/0002-9343(90)90190-o. [DOI] [PubMed] [Google Scholar]
  23. Kociba R. J., Sleight S. D. Acute toxicologic and pathologic effects of cis-diamminedichloroplatinum (NSC-119875) in the male rat. Cancer Chemother Rep. 1971 Feb;55(1):1–8. [PubMed] [Google Scholar]
  24. Koury M. J., Bondurant M. C. Erythropoietin retards DNA breakdown and prevents programmed death in erythroid progenitor cells. Science. 1990 Apr 20;248(4953):378–381. doi: 10.1126/science.2326648. [DOI] [PubMed] [Google Scholar]
  25. Koury S. T., Bondurant M. C., Koury M. J. Localization of erythropoietin synthesizing cells in murine kidneys by in situ hybridization. Blood. 1988 Feb;71(2):524–527. [PubMed] [Google Scholar]
  26. Lacombe C., Da Silva J. L., Bruneval P., Fournier J. G., Wendling F., Casadevall N., Camilleri J. P., Bariety J., Varet B., Tambourin P. Peritubular cells are the site of erythropoietin synthesis in the murine hypoxic kidney. J Clin Invest. 1988 Feb;81(2):620–623. doi: 10.1172/JCI113363. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. LeRoy A. F., Lutz R. J., Dedrick R. L., Litterst C. L., Guarino A. M. Pharmacokinetic study of cis-dichlorodiammineplatinum(II) (DDP) in the beagle dog: thermodynamic and kinetic behavior of DDP in a biologic millieu. Cancer Treat Rep. 1979 Jan;63(1):59–71. [PubMed] [Google Scholar]
  28. Lee G. R. The anemia of chronic disease. Semin Hematol. 1983 Apr;20(2):61–80. [PubMed] [Google Scholar]
  29. Lim V. S., DeGowin R. L., Zavala D., Kirchner P. T., Abels R., Perry P., Fangman J. Recombinant human erythropoietin treatment in pre-dialysis patients. A double-blind placebo-controlled trial. Ann Intern Med. 1989 Jan 15;110(2):108–114. doi: 10.7326/0003-4819-110-2-108. [DOI] [PubMed] [Google Scholar]
  30. Lin A. C., Goldwasser E., Bernard E. M., Chapman S. W. Amphotericin B blunts erythropoietin response to anemia. J Infect Dis. 1990 Feb;161(2):348–351. doi: 10.1093/infdis/161.2.348. [DOI] [PubMed] [Google Scholar]
  31. Litterst C. L., Schweitzer V. G. Increased tissue deposition and decreased excretion of platinum following administration of cisplatin to cisplatin-pretreated animals. Cancer Chemother Pharmacol. 1984;12(1):46–49. doi: 10.1007/BF00255909. [DOI] [PubMed] [Google Scholar]
  32. Loya F., Yang Y., Lin H., Goldwasser E., Albitar M. Transgenic mice carrying the erythropoietin gene promoter linked to lacZ express the reporter in proximal convoluted tubule cells after hypoxia. Blood. 1994 Sep 15;84(6):1831–1836. [PubMed] [Google Scholar]
  33. Matsumoto T., Endoh K., Kamisango K., Akamatsu K., Koizumi K., Higuchi M., Imai N., Mitsui H., Kawaguchi T. Effect of recombinant human erythropoietin on anticancer drug-induced anaemia. Br J Haematol. 1990 Aug;75(4):463–468. doi: 10.1111/j.1365-2141.1990.tb07783.x. [DOI] [PubMed] [Google Scholar]
  34. Means R. T., Jr, Krantz S. B. Inhibition of human erythroid colony-forming units by gamma interferon can be corrected by recombinant human erythropoietin. Blood. 1991 Nov 15;78(10):2564–2567. [PubMed] [Google Scholar]
  35. Means R. T., Jr, Krantz S. B. Progress in understanding the pathogenesis of the anemia of chronic disease. Blood. 1992 Oct 1;80(7):1639–1647. [PubMed] [Google Scholar]
  36. Miller C. B., Jones R. J., Piantadosi S., Abeloff M. D., Spivak J. L. Decreased erythropoietin response in patients with the anemia of cancer. N Engl J Med. 1990 Jun 14;322(24):1689–1692. doi: 10.1056/NEJM199006143222401. [DOI] [PubMed] [Google Scholar]
  37. Miller C. B., Platanias L. C., Mills S. R., Zahurak M. L., Ratain M. J., Ettinger D. S., Jones R. J. Phase I-II trial of erythropoietin in the treatment of cisplatin-associated anemia. J Natl Cancer Inst. 1992 Jan 15;84(2):98–103. doi: 10.1093/jnci/84.2.98. [DOI] [PubMed] [Google Scholar]
  38. Naganuma A., Satoh M., Imura N. Prevention of lethal and renal toxicity of cis-diamminedichloroplatinum(II) by induction of metallothionein synthesis without compromising its antitumor activity in mice. Cancer Res. 1987 Feb 15;47(4):983–987. [PubMed] [Google Scholar]
  39. Nowrousian M. R., Schmidt C. G. Effects of cisplatin on different haemopoietic progenitor cells in mice. Br J Cancer. 1982 Sep;46(3):397–402. doi: 10.1038/bjc.1982.216. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Platanias L. C., Miller C. B., Mick R., Hart R. D., Ozer H., McEvilly J. M., Jones R. J., Ratain M. J. Treatment of chemotherapy-induced anemia with recombinant human erythropoietin in cancer patients. J Clin Oncol. 1991 Nov;9(11):2021–2026. doi: 10.1200/JCO.1991.9.11.2021. [DOI] [PubMed] [Google Scholar]
  41. Robins A. B., Leach M. O. Pharmacokinetics of therapeutic doses of isotopically labeled platinum antitumor agents in the mouse and rat. Cancer Treat Rep. 1983 Mar;67(3):245–252. [PubMed] [Google Scholar]
  42. Rossof A. H., Slayton R. E., Perlia C. P. Preliminary clinical experience with cis-diamminedichloroplatinum (II) (NSC 119875, CACP). Cancer. 1972 Dec;30(6):1451–1456. doi: 10.1002/1097-0142(197212)30:6<1451::aid-cncr2820300606>3.0.co;2-q. [DOI] [PubMed] [Google Scholar]
  43. Smith D. H., Goldwasser E., Vokes E. E. Serum immunoerythropoietin levels in patients with cancer receiving cisplatin-based chemotherapy. Cancer. 1991 Sep 1;68(5):1101–1105. doi: 10.1002/1097-0142(19910901)68:5<1101::aid-cncr2820680533>3.0.co;2-l. [DOI] [PubMed] [Google Scholar]
  44. Teicher B. A., Herman T. S., Holden S. A., Wang Y. Y., Pfeffer M. R., Crawford J. W., Frei E., 3rd Tumor resistance to alkylating agents conferred by mechanisms operative only in vivo. Science. 1990 Mar 23;247(4949 Pt 1):1457–1461. doi: 10.1126/science.247.4949.1457. [DOI] [PubMed] [Google Scholar]
  45. Teicher B. A., Holden S. A., Eder J. P., Brann T. W., Jones S. M., Frei E., 3rd Influence of schedule on alkylating agent cytotoxicity in vitro and in vivo. Cancer Res. 1989 Nov 1;49(21):5994–5998. [PubMed] [Google Scholar]
  46. Wiltshaw E., Kroner T. Phase II study of cis-dichlorodiammineplatinum(II) (NSC-119875) in advanced adenocarcinoma of the ovary. Cancer Treat Rep. 1976 Jan;60(1):55–60. [PubMed] [Google Scholar]
  47. Winearls C. G., Oliver D. O., Pippard M. J., Reid C., Downing M. R., Cotes P. M. Effect of human erythropoietin derived from recombinant DNA on the anaemia of patients maintained by chronic haemodialysis. Lancet. 1986 Nov 22;2(8517):1175–1178. doi: 10.1016/s0140-6736(86)92192-6. [DOI] [PubMed] [Google Scholar]
  48. el-Sharkawi A. M., Morgan W. D., Cobbold S., Jaib M. B., Evans C. J., Somervaille L. J., Chettle D. R., Scott M. C. Unexpected mobilisation of lead during cisplatin chemotherapy. Lancet. 1986 Aug 2;2(8501):249–250. doi: 10.1016/s0140-6736(86)92072-6. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES